Latest experiences from Latest experiences from coffee intervention trialscoffee intervention trials

Hubert KolbInstitute of Molecular MedicineInstitute of Molecular Medicine

University of Düsseldorf, GermanyUniversity of Düsseldorf, Germany

Jaakko TuomilehtoDepartment of Public Health

University of Helsinki, Finland

THE MEDIACENTER

Epidemiological data Possible mechanism

THE MEDIACENTER

Coffee consumption and the development of Type 2 diabetes

among the Finns who have the highest coffee consumption rate in the world

- 11.3 kg/year per capita

Incidence of type 2 diabetes by volume of coffee consumption

among men

Adjusted for age, exam year, BMI, SBP, smoking, education, physical activity, alcohol and tea consumption

Coffee consumption

Age and exam year adjustment

Multivariate adjustment

<=2 cups 1.00 1.00 3-4 cups 0.83 (0.54-1.25) 0.74 (0.48-1.14) 5-6 cups 0.88 (0.60-1.30) 0.71 (0.47-1.10) 7-9 cups 0.86 (0.53-1.39) 0.67 (0.40-1.14) >=10 cups 0.69 (0.40-1.19) 0.45 (0.25-0.81) P for trend 0.735 0.121

Incidence of type 2 diabetes by volume of coffee consumption

among women

Adjusted for age, exam year, BMI, SBP, smoking, education, physical activity, alcohol and tea consumption

Coffee consumption

Age and exam year adjustment

Multivariate adjustment

<=2 cups 1.00 1.00 3-4 cups 0.72 (0.49-1.04) 0.73 (0.50-1.08) 5-6 cups 0.49 (0.32-0.73) 0.40 (0.26-0.63) 7-9 cups 0.47 (0.25-0.87) 0.42 (0.22-0.79) >=10 cups 0.26 (0.08-0.85) 0.21 (0.06-0.70) P for trend 0.002 <0.001

Coffee (cups) <=2 3-4 5-6 7-9 >=10

Adjusted for sex, exam year, BMI, SBP, smoking, education, physical activity, alcohol and tea consumption.

1.0

0.8

0.6

0.4

0.2

0.0

Age >50

Age <50

Incidence of type 2 diabetes by volume of coffee consumption among subjects

by age group

Coffee (cups) <=2 3-4 5-6 7-9 >=10

Adjusted for age, sex, exam year, SBP, education, smoking, physical activity, alcohol and tea consumption.

1.0

0.8

0.6

0.4

0.2

0.0

BMI >=30

BMI <30

Incidence of type 2 diabetes by volume of coffee consumption

among obese and non-obese subjects

van Dam 2002 Lancet 360:1477, Saremi 2003 Diabetes Care 26:2211, Reunanen 2003 Lancet 361:702,Rosengren 2004 J Intern Med 255:89, Salazar-Martinez 2004 Ann Intern Med 140:1, Tuomilehto 2004JAMA 291:1213, Carlsson 2004 Int J Epidemiol 33:616, van Dam 2004 Diabetologia 47:2152, Greenberg 2005 AJCN 84:682, van Dam 2006 Diabetes Care 29:398, Iso 2006 Ann Intern Med 144:554, Pereira 2006Arch Intern Med 166:1311, Smith 2006 Diabetes Care 29:2385, Paynter 2006 Am J Epidemiol 164:1075, Schulze 2007 Diabetes Care 30:510, Hamer 2008 Brit J Nutr 100:1046, Odegaard 2008 AJCN 88:979, van Dieren 2009 Diabetologia 62:2561, Sartorelli 2010 AJCN 91:1002, Boggs 2010 AJCN 92:960, Oba 2010 Br J Nutr 103:453, Goto 2011 Diabetes 60:269, Zhang 2011 Nutr Metab Cardiovasc Dis 21:418, Lin 2011 Eur J Clin Invest 41:659, Hjellvik 2011 22:418.

Coffee consumption is associated with reduced diabetes risk

Summary estimate derived from 25 epidemiological studies:

1-2 cups per day: rel. risk approx. 0.9

3-4 cups per day: rel. risk approx. 0.8

≥ 5 cups per day: rel. risk approx. 0.6

? YES: Drinking coffee protects from diabetes

? NO: Coffee-associated lifestyle is protective,

people drinking coffee are “different”

Coffee consumption is associated with reduced diabetes risk

Is it a cause-effect relationship?

No beneficial effects in OGTT:

Modestly increased insulin resistance (caffeine!)

Coffee consumption tested in intervention trials

Single dose: effect on glucose metaboIism?

Graham 2001 Can J Physiol Pharmacol 79:559, Keijzers 2002 Diabetes Care 25:364, Johnston 2003 Am J Clin Nutr 78:728, Robinson 2004 J Nutr 134:2528, Petrie 2004 Am J Clin Nutr 80:22, Battram 2006 J Nutr 136:1276, Moisey 2008 Am J Clin Nutr 87:1254, van Dijk 2009 Diabetes Care 32:1023, Moisey 2010 Br J Nutr 103:833, Greenberg 2010 Diabetes Care 33:278, Beaudoin 2011 Crit Rev Food Sci Nutr 51:363, Olthof 2011 Nutr Metab (Lond) 8:10, Kätönen 2011 Eur J Nutr epub

Possible mechanismsChlorogenic acid is found in green coffee:

- An inhibitor of glucose-6- phosphatase that catalyzes the terminal reaction of glycogenolysis and gluconeogenesis, the two glucose-producing pathways in human liver.

- It also inhibits glucose transporters (Na+ -dependent glucose transporter) at the intestinal stage and may also inhibit the action of the α-Glucosidase enzyme.

No !

Coffee consumption tested in intervention trials

4-8 weeks coffee: effect on glucose metaboIism?

Kempf, Herder, Erlund, Kolb, Martin, Carstensen, Koenig, Sundvall, Bidel, Kuha, Tuomilehto 2010Am J Clin Nutr 91: 950-957Wedick, Brennan, Sun, Hu, Mantzoros, van Dam 2011 Nutrition Journal 10: 93

Coffee consumption tested in intervention trials

4-8 weeks coffee: effect on glucose metaboIism?

Kempf, Herder, Erlund, Kolb, Martin, Carstensen, Koenig, Sundvall, Bidel, Kuha, Tuomilehto 2010Am J Clin Nutr 91: 950-957

Coffee consumption tested in intervention trials

4-8 weeks of coffee: adiponectin increased!

Trial Adiponectin (µg/ml serum)

at baseline after 4-8 w coffee

Kempf 2010 (n=47) 7.96 8.42 (p<0.05)

Wedick 2011 (n=45) 7.80 8.24 (p<0.05)Epidemiological studies also find higher adiponectin levels with coffee drinking

(Adiponectin is a diabetes-protective factor)

Wiiliams 2008 Diabetes Care 31:504, Imatoh 2011 Eur J Nutr 50:279 (Li 2009 JAMA 302:179)

Caffeine Magnesium

Glucose metabolismThermogenesis ↑Satiety ↑

Insulin secretion ↑

Chlorogenic acid

Glucose absorption ↓Iron absorption ↓

N-Methylpyridinium (et al.)

Nrf2 ?

Fat: adiponectin ↑ Gut: GLP-1 ↑

Hypothalamus: anorexic peptides ↑

General: anti-oxidant defence ↑

Insulin sensitivity ↑Body weight ↓ Diabetes risk↓ Westererp-Platenga 2005 Obes Res 13:1195, Kovacs 2004 Br J Nutr:431, Pimentel 2009 Diabetol Metab Syndr 1:6, Boettler 2011 Mol Nutr Food Res 55:798, Bakuradze 2011 Mol Nutr Food Res 55:793, Paur 2010 Free Radic Biol Med 48:1218

P R O T E C T I V E M E C H A N I S M S

Nfr2 =

nuclear factor (erythroid-derived 2)-like 2

Integr Comp Biol. 2010 Nov;50(5):829-43.

Nrf2, a guardian of healthspan and gatekeeper of species longevity.Lewis KN, Mele J, Hayes JD, Buffenstein R.

AbstractAlthough aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

Integr Comp Biol. 2010 Nov;50(5):829-43. Nrf2, a guardian of healthspan and gatekeeper of species longevity.Lewis KN, Mele J, Hayes JD, Buffenstein R.

AbstractAlthough aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration.

We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

The role of the antioxidant and longevity-promoting Nrf2pathway in metabolic regulationGerasimos P. Sykiotis2, Ioannis G. Habeos2, Andrew V. Samuelson1, and Dirk Bohmann1

IIS: insulin and IGF signalling pathways